Archive | July, 2012

First they came for the communists,and I didn’t speak out because I wasn’t a communist.

Then they came for the trade unionists,and I didn’t speak out because I wasn’t a trade unionist.

Then they came for the Jews,and I didn’t speak out because I wasn’t a Jew.

Then they came for me,and there was no one left to speak out for me. Martin Niemöller regarding the Nazi purging of their many “targets”

Ordinarily, my Blog addresses medical issues. Today’s message is a hybrid; it deals with medicine, but also social matters. Specifically today’s focus is on the political and socioeconomic shifts already suffocating segments of our nation. I will not belabor the transition that medicine has already made. Medicare is by definition a socialist system. Make no mistake; our government dictates doctors’ and hospitals’ fees and annually ratchets them downward. The lay public typically ignores this fact because it does not impact them (at least not monetarily). People pay a lot for health insurance and have been led to believe they are entitled to free care. Unfortunately in order to provide such care, health care workers – doctors, hospitals, imaging centers…- have been dissected from our nation’s free market economy and forced to live in quite a different world. Doctors’ fees are not dictated by their skill or experience. Every doctor is considered the same, regardless of his or her expertise, additional training, better bedside manner, or even an indisputably greater skill-set. This construct contradicts our nation’s economic foundation. Hard work, dedication, and superior skill used to translate into the opportunity for economic success. That is no longer the case in medicine. Yet, no one outside of medicine blocked this theft of financial liberty because it was not in their immediate interest to fight that battle. And Medicine represents 16% of our GNP! So what kind of Nation do we live in? Is America still a Democracy?

Now our President’s Affordable Care Act is becoming a reality. I just received a letter from my health insurance company explaining why they are refunding me money from the premiums we have already paid. At first blush I was elated – after all, who wouldn’t want extra money. Then I considered the reason for the rebate. The Affordable Care Act instituted an 80/20 rule, demanding that only 20% of patients’ premiums be used for administrative purposes by health insurance companies. In other words, these companies have now entered my realm; the government is dictating what they can or cannot earn. Although I am no fan of the health insurance world, I see the signs that Niemöller spoke of. This is another group no one will fight for, and so they will lose. The banks are sure to be next; they have few friends so no one will stand by their side, as their businesses become government managed. Who will follow? Small businesses; the food industry; hotels; restaurants; the local ice cream store; your own or your child’s business???

The solution is simple. If we want to preserve a free-market economy; and a democratic society; if we want to continue to acknowledge that dedication, perseverance, sacrifice, drive, high aspirations, hope and good old fashioned hard work should be able to translate into financial success, then we must stand by even those people and businesses we dislike in order to protect them from losing their freedom. We need to understand that the more people, groups, and businesses lose their economic freedom, the more likely each of us will be to follow in their footsteps. Niemöller was right about the Nazis. Let’s appreciate his wisdom and heed his advice.

Today’s final post in this six-part series describes one FDA approved non-medication treatment for severely elevated LDL cholesterol, and three novel medications on the horizon.

LDL-Apheresis is a non-drug therapy for patients with vascular disease and LDL-C > 200. It is reserved for patients with a genetic disorder called Familial Hypercholesterolemia (FH), or those individuals who cannot tolerate standard medications but still have very high LDL levels. Therefore, this treatment is clearly not for everyone. In a manner similar to dialysis, patients are connected to a filtering machine through two IV lines. Blood is withdrawn from one arm, circulated through a series of filters and returned to the body through the other arm. Typically the procedure is performed every other week. Each treatment results in a 60% to 80% reduction in LDL particles. After treatments, the LDL will rise steadily until it can be lowered once again with another therapy. Although LDLs do increase after a treatment, studies have demonstrated a nearly 75% reduction in cardiovascular events when patients are treated with LDL-Apheresis. Thus, LDL-Apheresis is a viable option for high risk patients. I am very fortunate to be able to run one of the forty or so centers in the USA, and I am happy to say that not only is the procedure extraordinarily well tolerated, but also the lipid effects are nothing short of remarkable.

As for the medications on the horizon, three deserve immediate recognition: Mipomersen, Lomitapide, and REGN727. These are all currently “experimental” but deserve mention not just because they will likely soon be on the market, but because each one represents a truly fresh way to lower LDL.

Mipomersen, licensed by Genzyme, is a second generation antisense oligonucleotide that is administered weekly by injection. It dramatically lowers LDL. The English translation is that this drug thwarts our body’s LDL production mechanism at the DNA level. DNA’s job is to produce mRNA in order to translate DNA’s protein-producing knowledge into the actual creation of proteins. Mipomerson binds and inactivates the mRNA that carries the code for the essential protein in every LDL particle, apoB. Without apoB, LDL cannot be created. Mipomerson does not block cholesterol production; it stops our body from producing too many LDL particles. Very different from the way statins work!

Lomitapide – owned by Aegerion – works differently. The first step in normal LDL particle construction is the merger of apoB (a protein) with triglycerides (fats). Even within cells, fats do not float freely; they must be chaperoned from one place to another. (Remember, water – blood – and fat do not mix!) The chaperone for triglycerides in the intestinal and liver cells is called MTP, or Microsomal Triglyceride Transfer Protein. Lomitapide inhibits MTP; it is our first MTP inhibitor. By blocking the transfer of enough triglycerides to the essential apoB protein, defective LDL precursors are produced. Our bodies don’t like out-of the-ordinary substances, and so these precursors are rapidly destroyed. The result, dramatically decreased LDL (and triglyceride) levels.

Finally, there’s REGN727, a drug that is too young to bear a proper name. This agent utilizes yet another innovative approach to diminish LDL. If you recall from Part 4 of this series, LDL receptors bring LDL into cells. When we have a lot of LDL receptors on our liver cells, LDL levels fall, and our blood vessels are far better off. Our bodies produce a substance called PCSK9 whose role is to bind and inactivate LDL receptors. When PCSK9 levels are out of control, we destroy too many receptors and develop dangerously high levels of LDL. REGN727 is an antibody against PCSK9, so it stops our bodies from inappropriately destroying valuable LDL receptors. By doing so, it too lowers LDL. Of the three novel agents, this one is furthest from the market. It needs more thorough testing before it can be released. At this point though, confidence is high. Hopefully within a few years we will see all three of these agents helping millions of patients avoid experiencing heart attacks and strokes.

I hope you’ve enjoyed reading this series on Cholesterol and Vascular Disease as much as I’ve enjoyed writing it. Thanks for tuning in. Next week…

Cook rice according to package directions. Transfer rice to a large bowl; fluff with a fork. Cool. Add chicken, carrot, onions, 2 tablespoons peanuts, 2 tablespoons cilantro, and salt to rice; toss to combine. Combine juice and remaining ingredients in a small bowl; drizzle over rice mixture and toss to combine. Sprinkle each serving with remaining peanuts and cilantro; serve with lime wedges.

Last week, in part 4 of this blog series we spoke about the statins. This week we will look at other cholesterol medications. Another very effective method for decreasing LDL is by combining a statin with other drugs.

Medications

One of the most effective add-on medications is Ezetimibe. This medicine works by blocking cholesterol absorption in our small intestine. It’s not just the cholesterol we eat that is blocked; more importantly it’s the enormous amount of cholesterol that is recycled daily between our liver and intestine. At this point, clinical trials have failed to demonstrate a reduction in heart attack and stroke by using Ezetimibe. Still, many lipid specialists (me included) believe that future trials will demonstrate its importance in particular patient populations.

Another important class of cholesterol-lowering drug is called the bile acid sequestrants. Welchol is the most commonly utilized of these medications. By blocking the reabsorption of bile acids in our intestine our liver is forced to produce more bile acids from their precursor, cholesterol. Interestingly, WelChol also has the added benefit of lowering blood sugar and increasing HDL. Patients with very high triglycerides should be careful of this medication because it can increase triglycerides further. Like Ezetimibe, WelChol is best used in combination with a statin.

Niacin, vitamin B3, is also often used in cholesterol management. It’s best known for its impact on raising HDL and lowering triglycerides. Niacin also has an effect on LDL however. It increases LDL particle size, and by so doing, can actually decrease LDL particle number. Niaspan is the pharmaceutical version of niacin that is most commonly utilized by the physicians. It’s method of action is poorly understood and quite complex. Like WelChol and Ezetimibe, niacin is also best used in conjunction with a statin.

Fenofibrates represent yet another class of medications that is used for cholesterol management. Their dominant effect is to lower triglycerides and raising HDL. At this point clinical trials have not found them to be effective in decreasing cardiovascular events, but they are improving lipids and lipoproteins.

The active ingredients in fish oil, DHA and EPA, can also have an effect on lipids and lipoproteins. They can lower triglycerides, increase HDL, and sometimes increase particle size and by so doing decrease particle number. In patients with very high triglycerides, fish oils can at times increase LDL cholesterol. Their method of action is also quite complex and beyond the scope of this blog.

Diet and Exercise

In managing cholesterol abnormalities we should never neglect the value of diet and exercise. A healthful diet will unquestionably improve your lipid and lipoprotein profile. Even when taking a statin, a healthful diet must be maintained. In fact, there is a specific dietary program called the Portfolio Diet that is geared specifically to lower cholesterol. Exercise can also benefit your lipid and lipoprotein profile. Daily exercise for 30-60 min. can significantly decrease your LDL particle number, increase your HDL, and lower your triglycerides. The bottom line, if you’re physically capable, exercise every day.

A few other cholesterol management strategies are either in the pipeline, or utilized only in very high risk patients. They will be the subject of next week’s blog, part 6 in this series, Cholesterol and Vascular Disease.

It has been unequivocally established that high levels of LDL can lead to heart attacks and strokes. Parts 1- 3 of this blog described the history of cholesterol, the superiority of LDL particles over LDL cholesterol, and the pathophysiology associated with an overabundance of LDL particles. In addition to our understanding of the biological process whereby LDL particles cause vascular disease, we also have a plethora of clinical trials demonstrating the efficacy of lowering LDL.

Everyone–lay people, physicians, and scientists–is plagued by the overabundance of clinical trials involving all aspects of health and medicine, many of which clearly contradict one another. In order to practice medicine in a fashion that appropriately considers the outcomes of these clinical trials, one must find a way to make sense of them. My approach has been to evaluate the clinical trials not just individually, but as a whole. I look for trends. When studies repeatedly reach the same conclusions (especially when they pathophysiologically “make sense”) I feel much more comfortable concluding that they are correct. In the case of LDL we find a commonality that is indisputable. The studies repeatedly demonstrate that statins–a class of cholesterol lowering medications I will momentarily describe–uniformly decrease the risk of cardiovascular events by about 30%. This event reduction is consistent among patients in the setting of both primary and secondary prevention. And so we must listen to the studies and lower our patients’ LDLs accordingly.

Statins are the class of medication for cholesterol management that unequivocally possess the greatest amount of science supporting their use. These medications work by blocking a critical enzyme in our body’s production of cholesterol. In response to lower levels of cholesterol within our cells, the cells increase surface receptors to bring in more LDL particles. The result is a diminution in the number of LDL particles – as well as the LDL cholesterol – in our bloodstream. Read More…

It is time to bury the debate and resuscitate the dialectic. Mankind’s greatest thinkers, Greek philosophers such as Plato, Aristotle and Socrates, held the compass to truth. They understood that dialectic, not debate could enable educated and free-thinking people possessing opposing viewpoints to peacefully and congenially work together for the sole purpose of discovering truth. Winning was not the goal. We have lost their vision. Instead we have become a nation of fighters. We argue our viewpoints with tenacity and oftentimes utter disrespect for our opponents. The fight has become more valuable than the truth. Consequently we have trapped ourselves in an intellectual whirlpool wherein we desperately tread water, struggling to stay afloat but never making any headway toward the safety of the shore.

I see this in different aspects of our culture. In medicine the alternative practitioners condemn the traditional doctors often claiming money to be their only motivation. They effortlessly and unfoundedly dismiss well-structured clinical trials and large bodies of clinical evidence as “flawed”. In doing this they often dispose of the baby with the bathwater, and steer patients away from potentially life-saving therapies. The traditional doctors are no better. They misrepresent evidence based medicine as though it were “truth based”. In so doing they cite an evidentiary void as cause for dissuading patients with chronic and sometimes incurable ailments from seeking alternative and potentially beneficial strategies. They dismiss anecdotes, clinical intuition, and even well-accepted human physiology as meaningless evidence for shaping health care strategies. In the end, we all suffer. The bilateral intransigence leads to cognitive and creative stagnation, precluding possibilities that might have led to better patient outcomes.

Politics is even worse. Both inter – and intra-party discord reigns king. While everyone would agree that our nation is experiencing desperate times, where do we see our leaders and the public engaging in discourses to find true answers? How long has it been since we have witnessed a genuinely respectful discourse, its sole intent to discover a solution? Debates abound; gaffs draw more attention than brilliance; solutions to our problems are instantly met with blind criticism, and no one seems to be able to acknowledge a valuable perspective when it is voiced by a member of the “opposing” party. We preach about reaching across the aisle yet there is no evidence of any sincere attempts to do so. Yes, in politics politicians must get elected and then re-elected. But they are charged with expressing their true viewpoints, minus acerbity, and then we the people are supposed to select our representatives, those individuals who will best represent our beliefs and our ideals. We know that our politicians have become far too concerned with their own political well-being. This is why they fail us. This is where we are today.

Last week we discussed the relevance of LDL particles, emphasizing their role as the main drivers of vascular disease. We did not, however, discuss how they wreak such havoc upon our blood vessels. Today we will do so.

LDL particles do wonderful things. They transport cholesterol and triglycerides to various parts of our body for fuel, storage, or even to serve as building blocks for other important molecules. They even transport vitamin E to our brains in order to enhance growth and development in infants, and proper brain function in adults. So how can something so good, be so bad? The answer lies in numbers. The aphorism “too much of a good thing can be bad” applies perfectly to LDL particles; they are necessary for a healthy body, but only in small quantities. The numbers most of us possess are so far out of range, they are literally killing us. But how? What happens when these tiny particles make their way beneath the delicate yet vital single cell layer (called the endothelium) that lines our blood vessels?

When LDL particles penetrate the boundary that separates blood from the blood vessel wall, they often cause a chain reaction that leads to plaque accumulation.

First they become oxidized. Oxidation leads to activation of an enzyme called LpPLA2 (lipoprotein associated phospholipase A2). Enzymes are biological molecules that initiate chemical reactions. In this case, LpPLA2 destroys a type of fat (a phospholipid) that sits within the surface membrane of LDL particles. The fat is broken in two, creating two independent but highly inflammatory elements – an oxidized fatty acid and Lyso-phosphatidylcholine (Lyso-PC). These “freed” fats summon other agents of atherogenesis (plaque formation) – adhesion molecules and cytokines are released bringing in specialized white blood cells called macrophages which then consume the oxidized LDL particles. As more oxidized particles are consumed, the macrophage weakens and ultimately dies, releasing its atherogenic contents and essentially pouring fuel on the fire beneath the endothelium. Other “bad” substances are also produced – MMPs (matrix metalloproteinases) for example chew away at the cap that has formed over the budding plaque in an attempt to contain the fire below. As MMPs thin the cap it becomes more likely to tear. (Dr. Abela, Professor and Chief of Cardiology at MSU produced spectacular images of cholesterol crystals helping MMPs tear through the thinning cap. Remember, cholesterol that floats freely will crystallize. Once the cap tears, the fire rages into the vessel lumen (where our blood is freely flowing in order to bring nourishment to the tissues it feeds – in this case the heart muscle). The blood in turn attempts to quench the fire, but by doing so produces a blood clot, which in turn can entirely block the bloods passage. The end result – a heart attack and death of heart muscle. And it all started with the excessive LDL particles! Next week we will discuss methods to lower LDL particles to diminish our risk of heart attacks.